What is the differential diagnosis and management for a patient with rheumatoid arthritis (RA) on azathioprine, presenting with bicytopenia, severe anemia, leukopenia, and thrombocytopenia?

Azathioprine-Induced Bone Marrow Toxicity in Rheumatoid Arthritis

This patient's bicytopenia is most likely azathioprine-induced myelosuppression, and the drug must be discontinued immediately. 1

Differential Diagnosis

Primary Consideration: Azathioprine-Induced Myelotoxicity

• Azathioprine causes leukopenia in 28% of rheumatoid arthritis patients overall, with severe leukopenia (WBC <2500/mm³) occurring in 5.3% of RA patients specifically 1
• Myelotoxicity can develop at any time during treatment (range 2 weeks to 11 years), occurring either suddenly or over several months 2
• Pancytopenia from azathioprine is uncommon but potentially lethal, with a 2% mortality rate in severe cases 2, 3
• Patients with TPMT (thiopurine methyltransferase) or NUDT15 deficiency are at dramatically increased risk for severe, life-threatening myelosuppression 1, 4

Other Considerations to Exclude

• Drug interactions: Concomitant allopurinol, aminosalicylates (sulfasalazine), ACE inhibitors, or co-trimoxazole can exacerbate azathioprine-induced leukopenia 1
• Rheumatoid arthritis-related: Felty's syndrome (RA with splenomegaly and neutropenia), large granular lymphocyte leukemia 5
• Bone marrow infiltration: Lymphoproliferative disorders (lymphoma risk 0.5% in azathioprine-treated RA patients) 1
• Nutritional deficiencies: Megaloblastic anemia from B12/folate deficiency, though azathioprine itself can cause megaloblastic changes 6
• Infections: Viral infections (HIV, HCV, CMV) causing cytopenias 5

Immediate Management

Step 1: Discontinue Azathioprine Immediately

• Stop azathioprine now—do not wait for test results 1, 2
• With Hb 7.0 g/dL, ANC <1000/mm³, and low platelets, this represents severe myelosuppression requiring urgent intervention 1

Step 2: Assess Infection Risk and Initiate Prophylaxis

• The risk of infection increases significantly when neutrophil counts fall below 500/mcL, with 10-20% risk at counts below 100/mcL 7
• Check for fever; if present, initiate empiric broad-spectrum antibiotics immediately (anti-pseudomonal β-lactam such as piperacillin-tazobactam or carbapenem) 7, 1
• Consider antimicrobial prophylaxis even if afebrile given severe neutropenia 7
• Educate patient to report fever, signs of infection, unusual bleeding, or bruising immediately 1

Step 3: Supportive Care

• Transfuse packed red blood cells for symptomatic anemia (Hb 7.0 g/dL) 3
• Platelet transfusion if active bleeding or platelet count <10,000/mm³ 2
• Consider G-CSF (granulocyte colony-stimulating factor) for severe neutropenia with infection or high infection risk 3

Step 4: Laboratory Monitoring

• Complete blood count with differential daily until counts stabilize, then twice weekly 1, 2
• Peripheral blood smear to evaluate cell morphology and exclude other causes 5
• Reticulocyte count to assess bone marrow response 3
• Comprehensive metabolic panel, LDH, haptoglobin to exclude hemolysis 5

Step 5: Diagnostic Workup

• TPMT genotyping or phenotyping and NUDT15 genotyping to identify genetic predisposition to azathioprine toxicity 1, 4
  • Note: TPMT phenotyping (enzyme activity) is unreliable if recent blood transfusions received 1
  • TPMT testing explains only 27% of azathioprine-induced leukopenia cases, so normal results do not exclude drug toxicity 5
• Bone marrow aspiration and biopsy if counts do not improve within 2-4 weeks or if alternative diagnosis suspected 2, 3
• Exclude drug interactions: Review medication list for allopurinol, febuxostat, sulfasalazine, mesalazine, ACE inhibitors, co-trimoxazole 1
• Viral serologies (HIV, HCV, CMV) if risk factors present 5

Expected Recovery Timeline

• Dose reduction or withdrawal typically results in reversal of toxicity 1
• Counts usually begin improving within 1-2 weeks after drug discontinuation, with full recovery in 2-8 weeks 2, 3
• If recovery is delayed beyond 4 weeks, consider bone marrow examination to exclude other pathology 3

Alternative Immunosuppression for RA

Once counts recover, consider alternative agents for RA management:

• Methotrexate (if not already tried or contraindicated) 8
• Biologic DMARDs (TNF inhibitors, rituximab, tocilizumab) 8
• JAK inhibitors (tofacitinib, baricitinib) 8
• Corticosteroids as bridge therapy during transition 8

Critical Pitfalls to Avoid

• Do not restart azathioprine in this patient—the risk of recurrent severe myelosuppression is too high 1, 2
• Do not delay antibiotic therapy if fever develops—febrile neutropenia is a medical emergency 7, 1
• Do not assume normal TPMT testing excludes azathioprine toxicity—most cases occur in patients with normal TPMT 5
• Do not overlook drug interactions—allopurinol requires azathioprine dose reduction to 25% of usual dose if used concomitantly 1
• Monthly CBC monitoring (as recommended for maintenance) is insufficient—severe myelosuppression can develop suddenly between monthly checks 5, 2